title: A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.
authors.affiliation: Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohte
authors.forename: Masashi
authors.initials: M
authors.lastname: Shin
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasanuma
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yoneyama
authors.forename: Masumi
authors.initials: M
authors.lastname: Akita
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikebuchi
authors.forename: Eijiro
authors.initials: E
authors.lastname: Jimi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Maruki
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Akira
authors.initials: A
authors.lastname: Namba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Owan
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoda
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Furuya
authors.forename: Jyunji
authors.initials: J
authors.lastname: Kamizono
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakashima
authors.forename: Takafumi
authors.initials: T
authors.lastname: Susami
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Haga
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Komori
authors.forename: Takenobu
authors.initials: T
authors.lastname: Katagiri
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D051379:Mice; D009154:Mutation; D009221:Myositis Ossificans / Q000235:genetics* / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I